Derivatives of 2:3-dihydro-4-methyltfuro(3:2-c) quinoline and preparation thereof



ring closure, such as methylffuro to form a diazonium'oompound that subsequently Patented Aug. 25 1953 Q ICE 2,650,229 DERIVATIVES or 2:3-DIHYDRO-4-METHYL- FUao(s:2-c) QUINOLINE TTON THEREOF Helmut Timmler, Hans H Breitner, Wuppertal- "signors to Schenley AND PREPARA- Andersag, and Stephan Elberfeld, Germany, as- Industries, Inc.,

New York,

N. Y., a corporation of Delaware N 0 Drawing. Application May 28,1951, Serial No. 228,765 In Germany May 27, 1950 3 Claims. (01. 260-488) This invention relates generally to thesynthesis of;:novel organic chemical compounds and, more particularly, it is concerned withthe synthesis of polynu-clear heterocyclic compounds useful in chemotherapy.

This application is related to Your copending application Serial No. $228,761 as a companion application for isomerides of the :sameseries of compounds. These compounds have interesting and useful properties making them suitable for use in chemotherapy particularly as analgesics, stimulants and amoebieides. This application is similarly related to our copending application Serial No. 228,762 also filed on May 28,1951, disclosing the sulfur isologs of this series of compounds.

The novel compounds of this "invention may be regarded as derived from 2:3-dihydro-4- methyl-furo(3:2-c) quinoline, which is represented by the formula:

o-oHR Di -a y wherein R and R are alkyl groups.

In accordance with the process of thisinvention, these novel compounds are obtained by condensing an aliphatic 'ketone with a bz-hydrazine 2 alkyl 2:3 dihydro-4-methyl-furo (3:2-c)quinoline to form the corresponding ketone hydrazone, then cyclizing this compound, by treatment with a reagent capable of effecting glacial acetic acid, dilute or concentrated mineral acids or zinc chloride, whereby the desired finalproduct is obtained. The hydrazino starting material may be produced'easily by nitration and subsequent reduction of a 2 alkyl 2:3-dihydro-4-methyl-furo (3:2-c)quinoline yielding an amino compound that can be converted 'to the hydrazino compound, or, alternatively, it may be obtained by treating a bz-amino =2 alkyl-2:3-dihydro-4- (3:2.-c)quinoline with nitrous acid compounds. These reactions may be summarized, in'outline form, as follows (I) o-onn 11 'O-CHR CH! '11 may be reduced to the corresponding hydrazine-* HNJO:

'CHa

OIN

l (H) reductioh \N/ CH;

wherein R, R and R" are alkyl groups, not necessarily the same, either R oriR being comprised of at least 2 carbon atoms and R is an, alkyl group that is the first lower 'homolog of, that alkyl group, R or R", that comprises at least2 carbon atoms.

While the principles of this invention will be fully grasped from the-foregoingv by those versed. in the methods of synthesis of organic compounds, an illustrative example herewith follows, provided by way of explanation merely, and without any intention "that the invention will belimited thereby, for the operations described may be applied with like results to related start ing materials.

' moiety may be varied at choice.

. if the 'alkylene group is this invention, what About 21.4 grams of 2z3-dihydro-2z4-dimeth- 'yl-S-aminofurofii 2-0) quinoline (VIII) which may be prepared by cyclizing the intramolecularly rearranged allyl ether of the product obtained by cyclizing the hydrolyzed Schifis base condensation product of p-aminoacetanilide and acetoacetic ester, are dissolved in about 170 cc.

of concentrated hydrochloric acid and the amino compound is diazotized with 6.9 grams of sodium nitrite in the usual manner. This diazo-solution is added, in portions, to a solution of 45 grams of stannous chloride in 45 cc. of concentrated hydrochloric acid, at a temperature below 5 C., and the mixture is. stirred for a brief period of time thereafter. Then the solution is poured into a: caustic soda solution and the mixture is extracted with methylene chloride. The hydrazino compound (IX) thus obtained melts at 162 C. By condensing this hydrazine compound (IX) with methylethylketone in an alcoholic solution, with heating of the mixture on a waterbath for a half hour, the corresponding hydrazone (X) is obtained.

Approximately 25 grams of introduced into half a liter of 20% hydrochloric acid and the mixture is heated on the waterbath for half an hour. On cooling, the hydrochloride of the indole forms, crystallizes. It is more easily soluble in water than it is in hydrochloric acid. The melting point of the free base (XI) is 244 C.

By suitable selection of the ketone to be used,

this hydrazone are" derivative (XI) which the substituent alkyl groups of the pyrrolo 7:

Similar modification of the alkyl substituent of the furano moiety may be effected through selection of the reagent used in the synthesis of the alkyleneoxy precursor of the starting amino compound, i. e., allyl, the furano alkyl substituent group will be methyl, and so on in the homologous series, as higher alkenyl groups are present, higher alkyl groups are found in the'final product. I

Having thus described the subject matter of it is desired to secure by Letters Patent is: V

p 1. As a novel composition of matter, a chemi- &cal compound represented by the formula:

4 2. Process for the synthesis of organic chemical compounds that is represented as follows:

o-o11.cm T--on.om CH1 CH3 HRN Hts?) om then ,CH: N," 81101: N 1 N, .Nm 11 moocoycmoml o-oncm OCH.CH:

CH5 H01 1 N.NH

enters III characterized in that the bz-amino-furo-quinoi line starting material I is diazotized in an aqueous acidic solvent medium to produce the corresponding bz-diazo intermediate which is reduced in the cold with stannous chloride in an aqueous acidic solvent medium to yield the corresponding bz-hydrazino intermediate II which is condensed with methylethylketone by heating it therewith in an alcoholic solvent medium to obtain the corresponding bz-keto-hydrazone intermediate III which is cyclized to produce the desired final product by heating with hydrochloric acid.

3. Process for the synthesis of organic chemical compounds that is represented as follows:

STEPHAN BREI'INER.

References Cited in the file of this patent Fieser et 9.1.; Organic Chemistry (D. 0.

Heath a d Geneva 9 a yield the corresponding. 

1. AS A NOVEL COMPOSITION OF MATTER, A CHEMICAL COMPOUND REPRESENTED BY THE FORMULA: 